Over the past twenty years, the Genetic Epidemiology Unit at the Queensland Institute of Medical Research, under the direction of Dr Nick Martin, has conducted large scale genetic epidemiologic studies on a wide range of psychiatric phenotypes. These studies have exploited the Australian Twin Registry (established by N. Martin in 1978 with the first 15,000 pairs) and have come out of a series of NIAAA, NIDA and NIMH funded collaborative programs with US colleagues, notably Drs A. Heath and R. Todd at Washington University, St Louis. These include projects on the genetics of anxiety &depression (3000 subjects), alcohol dependence (5000), nicotine dependence (5000), opioid dependence (3000 - 60% complete) and ADHD (4000 -just starting). Often, as in the anxiety &depression collection for the current proposal, blood for DNA is obtained from sibships selected from a much larger set of phenotyped individuals, using an EDAC (extreme-discordant and concordant) design. In addition our Genome laboratory hosts and supervises the genotyping requirements of the largest schizophrenia genetics project in Australia directed by Dr Bryan Mowry. The common strategy we have applied is to perform genome-wide genetic linkage studies followed by fine-mapping in appropriate regions. In the present proposal we take a more direct approach by targeting known genetic variations in a set of 605 candidate genes for psychiatric disease in which the variants potentially alter a target site for microRNAs, a critical set of genes involved in control of gene expression and development. Thus much of our work is directed towards understanding fundamental causes of some of the most debilitating disorders in human health and which represent the major drain on public health throughout the world. These behavioral disorders represent some of the most recalcitrant public health issues which remain resistant to treatment and amelioration. Even where there may be effective therapies the mechanism of action is usually unknown. Our genetic strategies focus on identifying the inherited genetic c